Gitelman syndrome with primary hyperparathyroidism: A case report

Background: Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy, typically devoid of hypercalcemia. Herein, we described one patient of GS presenting with hypercalcemia concomitant with primary hyperparathyroidism (PHPT). Methods: On September 28, 2020, a middle-aged female patient was admitted to our hospital with a 12-year history of hypokalemia and hypomagnesemia. Laboratory examinations unveiled hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hypocalciuria, and gene sequencing revealed a homozygous mutation in SLC12A3 (c.179C > T [p.T60M]). Subsequently, the diagnosis of GS was confirmed. In addition, the patient exhibited hypercalcemia and elevated levels of parathyroid hormone. Parathyroid ultrasound revealed left parathyroid hyperplasia, consistent with PHPT. Following aggressive treatment with potassium chloride and magnesium oxide, her serum potassium rose to 3.23 mmol/L, serum magnesium was 0.29 mmol/L, and her joint pain was relieved. Results: Based on the patient’s medical history, laboratory findings, and gene sequencing results, the definitive diagnosis was GS concomitant with PHPT. Conclusion: PHPT should be taken into consideration when patients diagnosed with GS exhibit hypercalcemia. While the serum potassium level readily exceeded the target threshold, correcting hypomagnesemia proved challenging, primarily because PHPT augments urinary magnesium excretion.


Introduction
Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy because of the inactivating mutations in the SLC12A3 gene, which encodes the sodium-chloride cotransporter of distal convoluted tubules.GS is characterized by chronic hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. [1,2][5][6][7] Primary hyperparathyroidism (PHPT) is typically characterized by hypercalcemia associated with inappropriately elevated PTH levels. [8]Therefore, in instances where hypercalcemia emerges in GS, consideration of PHPT is warranted.Herein, we described one patient of GS presenting with hypercalcemia concomitant with PHPT.

Case pressentation
On September 28, 2020, a 46-year-old female patient was admitted to our hospital presenting with a 12-year history of hypokalemia and hypomagnesemia.She has manifested Written informed consent was obtained from the patient who participated in our study for publication of this case report and any accompanying images.A copy of the written consent is available for review by the editor of this journal.

The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.
Ethical approval was obtained from the ethics committee of Linping Campus, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.All procedures in this study involving consent to participate were performed in accordance with the ethical standards of the institutional ethics and research committee.Written informed consent was obtained from the patient who participated in this study.
The author confirms that the manuscript is a unique submission and is not being considered for publication by any other source in any medium.Furthermore, the manuscript has not been published, in part or in full, in any form.symptoms including salt cravings, polydipsia, paroxysmal fatigue, and numbness in her hands since childhood.Twelve years ago, her prenatal care revealed hypokalemia with the lowest recorded serum potassium concentration being 2.2 mmol/L.Intermittent swelling and pain in both ankles commenced 2 years ago, and intermittent neck and left shoulder pain occurred 1 year ago.On August 18, 2020, the patient was hospitalized in a local hospital, with her blood pressure measured at 123/66 mm Hg postadmission.Laboratory tests revealed hypokalemia due to renal potassium wasting, hypomagnesemia, metabolic alkalosis, hypocalciuria, hypercalcemia, elevated PTH level, hyperreninemia (Table 1), and normal bone mineral density assessed via dual-energy X-ray absorptiometry of the hip joint and lumbar spine.Consequently, she was admitted to our hospital.
She had a history of type 2 diabetes for more than 10 years and was prescribed sitagliptin and glimepiride for glycemic control.Her parents were healthy and nonconsanguineous marriage.
Therefore, a next-generation sequencing-based panel was performed to identify the exact type of salt-losing tubulopathies.The method of gene sequencing was performed as previously reported. [9]A homozygous mutation in SLC12A3 (c.179C > T [p.T60M]) was identified (Fig. 1).The p.T60M mutation is a hotspot in the Chinese GS cohort. [10,11]o elucidate the etiology of hypercalcemia, further examinations were conducted: ultrasound of the parathyroid indicated left parathyroid hyperplasia; cervical spine computed tomography showed pyrophosphate deposition in the ligamentum flavum and calcification of the intervertebral disc annulus, while urinary tract ultrasound yielded normal findings.
Based on the patient's medical history, laboratory findings, and gene sequencing results, the definitive diagnosis was GS concomitant with PHPT.
Potassium chloride tablets (4.5 g per day) and magnesium oxide (450 mg magnesium per day) were administered to correct hypokalemia and hypomagnesemia.2017 Kidney Disease: Improving Global Results guidelines suggest that the serum potassium and magnesium levels of patients with GS should be maintained at a minimum of 3.0 and 0.6 mmol/L, respectively. [2]On October 26, 2020, the patient's joint pain was relieved, and her serum magnesium level rose to 0.35 mmol/L; however, hypomagnesemia persisted (Table 1).Therefore, the dose of magnesium was increased to 600 mg per day.However, achieving the target serum magnesium concentration remained challenging for the patient until December 14, 2020.

Discussion and conclusion
The patient, a middle-aged woman, had been afflicted with salt cravings, polydipsia, and paroxysmal fatigue since childhood.Laboratory tests showed hypokalemia due to renal potassium wasting, hypomagnesemia, metabolic alkalosis, and hypocalciuria.Gene sequencing identified a homozygous mutation in SLC12A3, indicating the presence of GS.In addition, she exhibited hypercalcemia, elevated PTH, and parathyroid hyperplasia, and PHPT was identified.Following magnesium supplementation, her joint pain subsided.
Hypomagnesemia constitutes a key clinical criterion for the diagnosis of GS.Generally, patients with GS do not present hypercalcemia, with impaired parathyroid gland function being proposed as a major factor associated with magnesium deficiency.In 1973, a study provided support for the hypothesis that magnesium depletion causes impaired synthesis or secretion of PTH. [6]In 1995, Bianchetti et al [3] confirmed the renal origin of magnesium depletion and disclosed that the relationship between PTH and ionized calcium concentrations was blunted in patients with GS, thus providing the first evidence that patients with GS have a disturbed secretion of PTH, which seems to be due to chronic hypomagnesemia in GS.In addition, this relationship was substantiated by the observation of a marked elevation in serum PTH level and the subsequent normalization of calcium levels in a patient with GS after intravenous infusion of magnesium salts.The steep rise in serum PTH induced by intravenous magnesium (detectable within 1 minute) indicated that PTH secretion, rather than synthesis, was impaired by magnesium deficiency. [4]In addition to the impaired release of PTH, Rude et al [5] noted that during the course of magnesium repletion, the serum calcium concentration failed to rise significantly within the initial 24 hours despite highnormal to greatly elevated serum PTH concentrations.The delayed response to endogenous PTH implies the existence of skeletal end-organ resistance to PTH. [5] Therefore, this patient with GS presented with profound hypomagnesemia, accompanied by hypercalcemia and elevated PTH levels, suggestive of PHPT.
In addition to elevated serum calcium levels, hypomagnesemia stands as a common electrolyte disturbance among patients with PHPT.Hypomagnesemia is present in approximately 25.1% of patients with PHPT. [12]15] The patient's cervical spine computed tomography showed pyrophosphate deposition in the ligamentum flavum and calcification of the intervertebral disc annulus.[18] Chondrocalcinosis, defined as calcification of the cartilage and identified by radiological or histological examinations, is a common feature of CPPD. [17,19,20]Several documented cases have reported CPPD within the ligamentum flavum, [21,22] as well as deposition in lumbar disc fibrocartilage. [23]PPD was identified as a manifestation of GS. [24] In GS, low serum magnesium results in calcium pyrophosphate formation in soft tissues and joints by inhibition of pyrophosphate hydrolysis and reducing crystal solubility. [25]A cohort of 57 patients with GS revealed a significant association between GS and extensive chondrocalcinosis, with the highest prevalence of cervical vertebra, particularly the C1-C2 level. [26]PPD can also be induced by hyperparathyroidism.A prospective study conducted in 1978 revealed the relationship between this endocrinopathy and calcium pyrophosphate dihydrate crystal deposition disease among patients with PHPT. [27]n a Japanese cohort of 132 patients with PHPT, chondrocalcinosis was identified in 6.1% of cases.These patients exhibited higher serum calcium levels and were older than those without this disorder, corroborating an earlier finding, [28] suggesting that chondrocalcinosis is caused by the cumulative impact of persistent hypercalcemia and age-related changes in articular cartilage. [29]A study conducted in the United States involving 25,157 patients diagnosed with CPPD, with an average age of 68.1 ± 12.3 years, demonstrated that hyperparathyroidism exhibited the most significant positive correlation with CPPD. [30]n 2011, the European League Against Rheumatism published a meta-analysis confirming a strong association between hyperparathyroidism and CPPD. [31]n summary, hypomagnesemia was a concomitant consequence of both GS and PHPT, making it challenging for the patient to achieve standard serum magnesium levels.CPPD was caused by the combined effects of PHPT and hypomagnesemia.Previously, we proposed parathyroid surgery for the patient.Meanwhile, we reinforced aggressive magnesium supplements to mitigate the deposition of calcium pyrophosphate resulting from hypomagnesemia.Subsequent to treatment, the patient experienced relief from symptoms and declined surgical intervention.This constitutes a limitation of this case report.
Despite hypocalciuria, hypercalcemia is generally absent in patients with GS due to magnesium deficiency.The presence of hypercalcemia in patients with GS warrants consideration of PHPT.Furthermore, PHPT can elevate urinary magnesium excretion, complicating the correction of hypomagnesemia in patients with GS.Considering the potential risk of worsening PHPT and hypercalcemia after the correction of hypomagnesemia, the management of GS requires individualized approaches.

a
Linping Campus, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China, b Division of Nephrology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Table 1
Laboratory tests.